Synthetic D- and L-enantiomers of 2,2-difluoro-2-deoxy-myo-inositol 1,4,5-trisphosphate interact differently with myo-inositol 1,4,5-trisphosphate binding proteins: Identification of a potent small molecule 3-kinase inhibitor
✍ Scribed by Stephen T. Safrany; Deborah A. Sawyer; Stefan R. Nahorski; Barry V.L. Potter
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 684 KB
- Volume
- 4
- Category
- Article
- ISSN
- 0899-0042
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✦ Synopsis
The ability of two enantiomeric fluoro-analogues of D-myo-inositol 1,4,5trisphosphate [Ins(1,4,5)P3] to mobilize intracellular Ca2+ stores in SH-SY5Y neuroblastoma cells has been investigated. ( -)-~-2,2-difluoro-2-deoxy-myo-Ins(1,4,5)P~ [~-2,2-F2 -Ins(1,4,5)P3] was a full agonist [ECm 0.21 pA4l and slightly less potent than ~-Ins(1,4,5)P3 FC50 0.13 pA4l.
( +)-i~-2,2-F21ns(l,4,5)P3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P3 receptor. r)-2,2-F2 -Ins(1,4,5)P3 mobilized Ca 2+ with broadly similar kinetics to Ins(1,4,5)P3 and was a substrate for Ins( 1,4,5)P3 3-kinase inhibiting Ins(1,4,5)P3 phosphorylation (apparent 4 = 10.2 pM) but was recognised less well than Ins(1,4,5)P3. 1~-2,2-F2-Ins(1,4,5)P3 was a potent competitive inhibitor of 3-kinase (Ki = 11.9 pM). Whereas ~-2,2-F2-Ins(1,4,5)P3 was a good substrate for Ins(1,4,5)P3 5-phosphatase, ~-2,2-F2 Ins(1,4,5)P3 was a relatively potent inhibitor (K, = 19.0 pM).